Variable region gene of heavy/light chain of anti-human hepatoma monoclonal antibody HAb 18 and use thereof

Abstract

The present invention relates to the anti-human hepatocarcinoma McAb HAb18 heavy chain and light chain variable region genes, the polypeptides encoded by the same, as well as to their use in the preparation of a medicament for diagnosing and treating tumors or inflammation diseases. Based on the heavy chain and light chain variable region genes, various novel small molecule genetic engineering antibodies, including single chain antibodies, chimeric antibodies, Fab antibodies and the like can be constructed and expressed for the diagnosis and treatment of hepatoma.

Description

[0001]This application is a National Phase 371 application of International Patent Application Ser. No. PCT / CN03 / 00188, filed Mar. 17, 2003, which claims priority from Chinese Patent Application No. 02114471.0, filed Mar. 15, 2002.FIELD OF THE INVENTION[0002]This invention relates to the anti-human hepatoma monoclonal antibody (McAb) HAb18 heavy / light chain variable region genes and the coded polypeptides thereof, and to the use of the genes and polypeptides in the preparation of medicaments for diagnosing and treating tumors or inflammatory diseases.BACKGROUND OF THE INVENTION[0003]Hepatoma is a common disease with high morbidity in China and Southeast Asia. Particularly in China, about 110,000 patients die of hepatoma each year, which holds 43% among the total dead hepatoma patients in the world. Therefore, it still requires comprehensive and profound research on hepatoma diagnosis and therapy. A variety of McAbs have been identified since hybridoma technology was established by K...

AI Technical Summary

Benefits of technology

[0012]For a chimeric antibody, the variable region of a mouse McAb may be linked with the constant region of a human Ig. Desirable efficacies in tumor therapy have been achieved by using such chimeric antibodies because these antibodies have reduced side effects such as the HAMA response while maintaining the specificity and affinity of a mouse McAb.

[0015]Multi-covalent miniantibodies mainly include double chain antibodies, (ScFv)2, Flex mini-antibodies, LD mini-antibodies, F(ab′)2, F(ab′)3, (ScFv)4, etc. The multi-covalent miniantibodies have good potential value in clinical applications because they have multiple antigen binding sites, high affinity, moderate molecule size, high ability to penetrate tumor tissues, and slow clearance rate in kidney.

[0018]Recombinant immunotoxins are produced by linking a gene for a toxin and a gene for an antibody and expressing the resultant gene. They have low non-specificity, are stable and safe in vivo and easily penetrate into tumors.

[0020]Using the polypeptides encoded by the heavy chain and light chain variable region genes of the invention as a carrier, various anti-cancer or anti-inflammation agents may be conjugated with said polypeptides so as to form immunoconjugates or targeted drugs. For example, the immunoconjugates or targeted drugs can be in the form of a conjugate of an antibody and a nuclide. Such a conjugate is able to direct the nuclide efficiently to local tumor tissues, reducing the damage to normal tissues incurred by irradiation during radiotherapy. The conjugate also allows a targeted diagnosis and treatment of tumors, termed radioimmunoimaging and radioimmunotherapy respectively. Nuclides normally used to conjugate with a monoclonal antibody include 125I, 131I, 111In, 90Y, 99Tcm, 188Re and 186Re, and the like.

[0021]The immunoconjugates or targeted drugs can also be in the form of a conjugate of an antibody and a chemotherapy drug. Such a conjugate directs the drug specifically to tumors, reducing the damage to normal tissues and the side effects caused by chemotherapy drugs. Chemotherapy drugs commonly used to conjugate with antibodies include alkylating agents such as phosphoramides, anti-metabolites such as methotrexate and 5-flurouracil, antibiotics such as adriblastine, epirubicin, cerubidin, leurocristine and mitomycin.

[0025]The immunoconjugates or targeted drugs can also be in the form of an immune liposome, in which a McAb is conjugated to the surface of a liposome. Because the liposome can encapsulate large amounts of drugs and the antibody can bind antigen specifically, immune liposomes with encapsulated drugs have improved specificity and efficacy.

Problems solved by technology

However, it is difficult to generate anti-hepatoma antibodies with high affinity and specificity by these methods because of the variation, instability or partial loss of the tumor antigenic epitopes.

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